There are many types of infections that can lead to cancer. One example is Epstein - Barr virus (EBV) which can lead Years after primary EBV infection, malignancies such as Burkitt’s lymphoma, nasopharyngeal carcinoma, and Hodgkin’s disease can emerge.This essay will cover the pathway of an EBV infection to Lymphoma.

EBV is a member of the herpes virus family. As with other herpes viruses, EBV is an enveloped virus that contains a DNA core surrounded by a capsule. EBV enters the host cell when one individual inhales vapour containing the virus. Primary infection begins at the oropharyngeal

epithelium. Upon infection, the individual remains a lifelong carrier of the virus. EBV is transmitted from host to host via saliva. However, not all EBV infection leads to cancer. To be oncogenic, EBV must maintain its viral genome in the cell, avoid killing the cell, and prevent the cell from becoming a target for destruction by the immune system. Finally, the virus must activate cellular growth control pathways.

To maintain viral DNA in the cell, EBV establishes latent infection in B lymphocytes. The EBV genome is maintained in these cells, either as a multicopy circular episome in the host cell or by integrating the viral DNA into the host genome. The virus thus ensures transmission to cell progeny when B lymphocytes replicate. EBV latent genes induce an activated phenotype in the infected B cells. Although these cells are not transformed, if they proceed unchecked or acquire oncogenic mutations, they can become neoplastic.
In normal individuals, cytotoxic T-cell which is a type of an antibody, responses against latent viral proteins prevent the expansion of these activated B cells. Through normal differentiation of these cells, EBV eventually enters the resting B-cell memory compartment. Only EBNA-1 is expressed in these cells. EBNA-1 is a sequence-specific DNA binding phosphoprotein that is required for the replication and maintenance of the EBV genome. It also has a central role in maintaining latent EBV infection Therefore, if the EBV growth-promoting latent genes are not expressed, the cells are not pathogenic. The also prevents frequent viral replication. Because cytotoxic responses to EBNA-1 are rare, EBNA-1-expressing lymphocytes escape immune surveillance. This then constitutes the viral reservoir. All cells contain the two

proteins – p53 and USP7 which work together to regulate cell growth. P53 is an important protein whose level in the cell determines whether cells will continue to proliferate or stop dividing and die. USP7 is a protein that binds to p53 and makes it stable. Under those conditions, cells stop growing and die, which is a natural state of cell regulation. Once EBNA1 is introduced to cells, however, this protein interferes with natural cell regulation by binding to USP7 and preventing its interaction with the p53 protein. Normally, p53 levels will increase in response to certain problems in the cell such as damaged DNA and this stops the cell from proliferating. Through binding USP7, EBNA1 keeps the p53 levels low so cells will continue to divide when they shouldn't, which means they're now more likely to develop into cancer.

Intermittently, these cells may enter the lytic cycle during which viral replication occurs and is accompanied by suppression of host protein synthesis with subsequent lysis/death of infected cells, releasing virions to infect more cells. With immune suppression, latently infected cells in the peripheral blood or persistently infected cells on the oropharynx increase in number. The final mandate of the virus in achieving oncogenecity is to activate intracellular signalling involved in control of proliferation. This is achieved through diverse virally expressed genes that stimulate multiple intersecting cellular transduction pathways.

Through the break through of science and technology, there are several antiviral compounds that have entered the clinical setting and have some anti-EBV activity.
The majority of these drugs are broad-spectrum anti-herpes virus and anti-cytomegalovirus virus agents that vary in their effectiveness against EBV. They include ganciclovir, famcyclovir, acyclovir, foscarnet, and cidofovir. Acyclovir and ganciclovir are not drugs of choice because, in EBV-associated lymphoid disorders, the virus is not replicating lytically, and the viral thymidine kinase enzyme is not expressed. These pharmacological agents are nucleoside analogues, which are converted by thymidine kinase to their monphosphate form and then by cellular enzymes to active triphosphates. The toxic metabolites are incorporated into DNA, leading to premature strand termination and apoptosis. To circumvent this problem, arginine butyrate, which can selectively activate EBV thymidine kinase genes in lymphoma cells, has been administered together with gancyclovir; this combination has demonstrated some efficacy in patients with EBV-associated lymph proliferations after solid organ transplantation.

The drawback to antivirals is that they have no influence on the underlying immunosuppression that favours EBV-driven tumorigenesis. Adoptive immunotherapy using EBV-specific Cytoxic T lymphocytes (CTLs), although it is time consuming and work intensive, may overcome this disadvantage. The CTLs can be taken from a donor and infused directly into the patient or expanded in vitro and then infused to re-establish

immunocompetence. Generation of EBV-specific CTLs from sero-positive healthy donors generally takes around 8 to 12 weeks. This method can be used as prophylaxis or to eradicate established disease in recipients who develop lymphoproliferative disorders after allogeneic haematopoietic stem cell transplants. These types of disorders are a particularly good target for such CTL therapy because the transformed cells, which are generally of donor origin, express all latent cycle virus-associated antigens.

Another way is by using monoclonal antibodies. The anti-CD20 monoclonal antibody designated Rituximab has enjoyed significant success in the treatment of a variety of CD20-expressing lymphomas. It is also an effective agent in the management of EBV-related lymphoproliferative disorders. A response rate of 69% has been reported in a group of transplant recipients. Because these lymphomas use InterLeukin-6 as a growth factor, anti-IL-6 monoclonal antibodies have also been tried. The reported response rate was 67%.

Therapy for EBV-associated tumours remains largely in the nascent stages, but research is being fuelled by the successful development of new antiviral and immunological approaches. To date, antiviral agents have received only perfunctory consideration, perhaps because of uncertainty regarding the role of EBV in maintaining established cancers. However, recent studies suggest that selected antiviral compounds, as well as therapeutic strategies such as use of adoptive immunotherapy with EBV-specific CTLs or administration of targeted monoclonal antibodies, hold considerable promise for the treatment of EBV-related malignancies.

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